Publications by authors named "Anke Hinney"

158 Publications

[Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation].

Z Kinder Jugendpsychiatr Psychother 2021 Jul 30. Epub 2021 Jul 30.

Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, LVR-Klinikum Essen, Kliniken und Institut der Universität Duisburg-Essen, Universitätsklinikum Essen.

Genetic Analyses of Complex Phenotypes Through the Example of Anorexia Nervosa and Bodyweight Regulation Genetics variants are important for the regulation of bodyweight and also contribute to the genetic architecture of eating disorders. For many decades, family studies, a subentity of so-called formal genetic studies, were employed to determine the genetic share of bodyweight and eating disorders and found heritability rates exceeding 50 % with both phenotypes. Because of this significant contribution of genetics, the search for those genes and their variants related to the variance in bodyweight and the etiology of eating disorders - or both - was commenced by the early 1990s. Initially, candidate genes studies were conducted targeting those genes most plausibly related to either phenotype, especially based on pathophysiological considerations. This approach, however, implicated only a few genes in the regulation of bodyweight and did not provide significant insights into the genetics of eating disorders. Driven by considerable methodological advances in genetic research, especially related to the introduction of so-called genome-wide association studies by the beginning of the 21st century, today more than 1,000 variants/loci have been detected that affect the regulation of bodyweight. Eight such loci have been identified regarding anorexia nervosa (AN). These results as well as those from cross-disorder analyses provide insights into the complex regulation of bodyweight and demonstrated unforeseen pathomechanisms for AN.
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http://dx.doi.org/10.1024/1422-4917/a000829DOI Listing
July 2021

Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55-87 years.

Sci Rep 2021 Jul 5;11(1):13852. Epub 2021 Jul 5.

Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany.

The heterozygous human Klotho KL-VS haplotype has been associated with improved cognitive performance but results are inconsistent. Here we assessed Klotho KL-VS haplotype and cognition using data from the third examination of the population-based Heinz Nixdorf Recall Study. We analyzed cognition tests (immediate and delayed word list, Trail-Making Test [TMT] part A and B, Maze test, interference condition of the Stroop color-word test, verbal fluency) and their associations with Klotho KL-VS haplotype. The Klotho KL-VS haplotype is classified by the V-allele at SNP rs9536314 (F352V) and the S-allele at SNP rs9527025 (C370S). Heterozygotes for the KL-VS haplotype were compared with non-carriers. Analyses were performed in 1812 subjects (55-87 years). We found consistent but only slightly lower performance in heterozygous carriers of the KL-VS haplotype in all tasks with Z-scores ranging between Z = - 0.042 (verbal fluency) and - 0.17 (TMT part A). Differences between carriers and non-carriers were similar for men and women for all tests but TMT part B (interaction contrast = 8.4 s (95% CI - 2.3; 19.1)). While cognition declined with age, we found an effect modification by age (55-65 years, 66-75 years, > 75 years). In the 66-75 years KL-VS heterozygous age group, lower performance was seen in memory, visual attention and motor speed. Contrary to our hypothesis, heterozygous carriers of the KL-VS haplotype did not show enhanced performance in cognitive tests in our study.
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http://dx.doi.org/10.1038/s41598-021-93211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257625PMC
July 2021

[Nutrition and mental health - how findings from genetic studies can support the identification of dietary effects].

Z Kinder Jugendpsychiatr Psychother 2021 Jun 11:1-10. Epub 2021 Jun 11.

Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, LVR-Klinikum Essen, Kliniken und Institut der Universität Duisburg-Essen.

Nutrition and mental health - how findings from genetic studies can support the identification of dietary effects Numerous studies indicate that dietary interventions could be an important approach to the prevention and treatment of mental disorders. However, conventional nutritional epidemiological approaches (e. g., observational studies and randomized controlled trials, RCTs) have specific limitations to consider when interpreting the results. This article examines whether genetic studies could help to establish a link between diet and the prevention of mental disorders. Furthermore, it examines whether it is possible to draw conclusions about causal relationships. This narrative review describes various approaches of genetic cross-phenotype studies and presents examples of their applications in nutritional psychiatry. In addition, it discusses specific requirements as well as the strengths and limitations of the respective approaches. To date, in the context of nutritional psychiatry, genetic correlation analyses, look-up analyses, and Mendelian randomization (MR) studies have been used for genetic crossphenotype analyses. Genetic correlation and look-up analyses provide initial evidence of possible overlap between specific mental disorders and metabolic pathways or specific nutrients. MR studies are used for detailed analyses that aim to identify causal relationships. However, MR is based on specific assumptions that must be met and considered when results are interpreted. Genetic cross-phenotype analyses are a useful amendment to conventional nutritional epidemiological research. In particular, positive results from MR studies provide an important fundament for identifying and developing suitable dietary interventions, which in turn increases the chance of success upon testing in subsequent RCTs. Accordingly, genetic cross-phenotype analyses are important instruments for increasing the efficiency in nutritional psychiatric research.
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http://dx.doi.org/10.1024/1422-4917/a000807DOI Listing
June 2021

Lack of Evidence for a Relationship Between the Hypothalamus-Pituitary-Adrenal and the Hypothalamus-Pituitary-Thyroid Axis in Adolescent Depression.

Front Endocrinol (Lausanne) 2021 24;12:662243. Epub 2021 May 24.

Department of Pediatrics, Division of Rare Diseases, St Josef-Hospital, and CeSER, Ruhr-University Bochum, Bochum, Germany.

In adults with major depressive disorder (MDD), a dysfunction between the hypothalamus-pituitary-adrenal (HPA) and the hypothalamus-pituitary-thyroid (HPT) axis has been shown, but the interaction of both axes has not yet been studied in adolescent major depressive disorder (MDD). Data from 273 adolescents diagnosed with MDD from two single center cross-sectional studies were used for analysis. Serum levels of thyrotropin (TSH), free levothyroxine (fT4), and cortisol were determined as indicators of basal HPT and HPA axis functioning and compared to that of adolescent controls by t-tests. Quantile regression was employed in the sample of adolescents with MDD to investigate the relationship between both axes in the normal as well as the pathological range of cortisol levels, considering confounders of both axes. In adolescent MDD, cortisol levels and TSH levels were significantly elevated in comparison to controls ( = <.001, = 1.35, large effect size, and = <.001, = 0.79, moderate effect size, respectively). There was a positive linear relationship between TSH and cortisol ( = .003, = 0.25, small effect size) at the median of cortisol levels (50 percentile). However, no relationship between TSH and cortisol was found in hypercortisolemia (cortisol levels at the 97.5 percentile). These findings imply that HPT and HPA axis dysfunction is common in adolescents with MDD and that function of both axes is only loosely related. Moreover, the regulation of the HPA and HPT axis are likely subjected to age-related maturational adjustments since findings of this study differ from those reported in adults.
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http://dx.doi.org/10.3389/fendo.2021.662243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181732PMC
May 2021

Rapid amelioration of anorexia nervosa in a male adolescent during metreleptin treatment including recovery from hypogonadotropic hypogonadism.

Eur Child Adolesc Psychiatry 2021 May 9. Epub 2021 May 9.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN.
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http://dx.doi.org/10.1007/s00787-021-01778-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106547PMC
May 2021

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Transl Psychiatry 2021 01 18;11(1):56. Epub 2021 Jan 18.

Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris, France.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.
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http://dx.doi.org/10.1038/s41398-020-01082-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814139PMC
January 2021

Alterations in B cell subsets correlate with body composition parameters in female adolescents with anorexia nervosa.

Sci Rep 2021 01 13;11(1):1125. Epub 2021 Jan 13.

Department of Mental Health, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany.

Anorexia nervosa (AN) is a severe eating disorder and often associated with altered humoral immune responses. However, distinct B cell maturation stages in peripheral blood in adolescents with AN have not been characterized. Treatment effects and the relationship between clinical and B cell parameters are also not fully understood. Here we investigated the phenotype of circulating B cell subsets and the relationship with body composition in adolescents with AN before (T0, n = 24) and after 6 weeks (T1, n = 20) of treatment. Using multi-parameter flow cytometry, we found increased percentages of antigen-experienced B cells and plasmablasts in patients with AN compared to healthy controls (n = 20). In contrast, percentages of CD1dCD5 B cells and transitional B cells with immunoregulatory roles were reduced at T0 and T1. These B cell frequencies correlated positively with fat mass, fat mass index (FMI), free fat mass index, and body mass index standard deviation score. In addition, scavenger-like receptor CD5 expression levels were downregulated on transitional B cells and correlated with fat mass and FMI in AN. Our findings that regulatory B cell subgroups were reduced in AN and their strong relationship with body composition parameters point toward an impact of immunoregulatory B cells in the pathogenesis of AN.
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http://dx.doi.org/10.1038/s41598-020-80693-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806719PMC
January 2021

Kurzzeitige Behandlung von Patient_innen mit Anorexia nervosa mit rekombinant hergestelltem Human-Leptin (Metreleptin): Rasch einsetzende positive Effekte auf Stimmung, Kognition und Verhalten.

Z Kinder Jugendpsychiatr Psychother 2021 01;49(1):1-5

Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, LVR-Klinikum, Kliniken/Institut der Universität Duisburg-Essen, Essen, Deutschland.

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http://dx.doi.org/10.1024/1422-4917/a000775DOI Listing
January 2021

Evaluation of Metabolic Profiles of Patients with Anorexia Nervosa at Inpatient Admission, Short- and Long-Term Weight Regain-Descriptive and Pattern Analysis.

Metabolites 2020 Dec 24;11(1). Epub 2020 Dec 24.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, 45147 Essen, Germany.

Acute anorexia nervosa (AN) constitutes an extreme physiological state. We aimed to detect state related metabolic alterations during inpatient admission and upon short- and long-term weight regain. In addition, we tested the hypothesis that metabolite concentrations adapt to those of healthy controls (HC) after long-term weight regain. Thirty-five female adolescents with AN and 25 female HC were recruited. Based on a targeted approach 187 metabolite concentrations were detected at inpatient admission (T), after short-term weight recovery (T; half of target-weight) and close to target weight (T). Pattern hunter and time course analysis were performed. The highest number of significant differences in metabolite concentrations (N = 32) were observed between HC and T. According to the detected main pattern, metabolite concentrations at T became more similar to those of HC. The course of single metabolite concentrations (e.g., glutamic acid) revealed different metabolic subtypes within the study sample. Patients with AN after short-term weight regain are in a greater "metabolic imbalance" than at starvation. After long-term weight regain, patients reach a metabolite profile similar to HC. Our results might be confounded by different metabolic subtypes of patients with AN.
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http://dx.doi.org/10.3390/metabo11010007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823299PMC
December 2020

A mendelian randomization study on causal effects of 25(OH)vitamin D levels on attention deficit/hyperactivity disorder.

Eur J Nutr 2021 Aug 27;60(5):2581-2591. Epub 2020 Nov 27.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 174, 45147, Essen, Germany.

Background: While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this relationship remains unclear.

Methods: We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls).

Results: Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878, p = 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D.

Conclusion: Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.
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http://dx.doi.org/10.1007/s00394-020-02439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275531PMC
August 2021

No Effect of Thyroid Dysfunction and Autoimmunity on Health-Related Quality of Life and Mental Health in Children and Adolescents: Results From a Nationwide Cross-Sectional Study.

Front Endocrinol (Lausanne) 2020 2;11:454. Epub 2020 Sep 2.

Department of Pediatrics and Center for Rare Diseases Ruhr CeSER, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany.

In adults, a significant impact of thyroid dysfunction and autoimmunity on health-related quality of life (HRQoL) and mental health is described. However, studies in children and adolescents are sparse, underpowered, and findings are ambiguous. Data from 759 German children and adolescents affected by thyroid disease [subclinical hypothyroidism: 331; subclinical hyperthyroidism: 276; overt hypothyroidism: 20; overt hyperthyroidism: 28; Hashimoto's thyroiditis (HT): 68; thyroid-peroxidase antibody (TPO)-AB positivity without apparent thyroid dysfunction: 61] and 7,293 healthy controls from a nationwide cross-sectional study ("The German Health Interview and Examination Survey for Children and Adolescents") were available. Self-assessed HRQoL (KINDL-R) and mental health (SDQ) were compared for each subgroup with healthy controls by analysis of covariance considering questionnaire-specific confounding factors. Thyroid parameters (TSH, fT4, fT3, TPO-AB levels, thyroid volume as well as urinary iodine excretion) were correlated with KINDL-R and SDQ scores employing multiple regression, likewise accounting for confounding factors. The subsample of participants affected by overt hypothyroidism evidenced impaired mental health in comparison to healthy controls, but SDQ scores were within the normal range of normative data. Moreover, in no other subgroup, HRQoL or mental health were affected by thyroid disorders. Also, there was neither a significant relationship between any single biochemical parameter of thyroid function and HRQoL or mental health, nor did the combined thyroid parameters account for a significant proportion of variance in either outcome measure. Importantly, the present study was sufficiently powered to identify even small effects in children and adolescents affected by HT, subclinical hypothyroidism, and hyperthyroidism. In contrast to findings in adults, and especially in HT, there was no significant impairment of HRQoL or mental health in children and adolescents from the general pediatric population affected by thyroid disease. Moreover, mechanisms proposed to explain impaired mental health in thyroid dysfunction in adults do not pertain to children and adolescents in the present study.
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http://dx.doi.org/10.3389/fendo.2020.00454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492205PMC
June 2021

Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects.

Transl Psychiatry 2020 08 27;10(1):303. Epub 2020 Aug 27.

Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen (LVR-Klinikum), University of Duisburg-Essen, Essen, Germany.

To examine the hypothesis that normalization of low circulating leptin levels in patients with anorexia nervosa ameliorates hyperactivity, three seriously ill females with hyperactivity were treated off-label with metreleptin (recombinant human leptin) for up to 14 days. Drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased in two patients. Surprisingly, depression improved rapidly in all patients. No serious adverse events occurred. Due to obvious limitations of uncontrolled case series, placebo-controlled clinical trials are mandatory to confirm the observed rapid onset of beneficial effects. Our findings suggest an important role of hypoleptinemia in the mental and behavioral phenotype of anorexia nervosa.
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http://dx.doi.org/10.1038/s41398-020-00977-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453199PMC
August 2020

The Role of Genetic Variation of BMI, Body Composition, and Fat Distribution for Mental Traits and Disorders: A Look-Up and Mendelian Randomization Study.

Front Genet 2020 21;11:373. Epub 2020 Apr 21.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Anthropometric traits and mental disorders or traits are known to be associated clinically and to show genetic overlap. We aimed to identify genetic variants with relevance for mental disorders/traits and either (i) body mass index (or obesity), (ii) body composition, (and/or) (iii) body fat distribution. We performed a look-up analysis of 1,005 genome-wide significant SNPs for BMI, body composition, and body fat distribution in 15 mental disorders/traits. We identified 40 independent loci with one or more SNPs fulfilling our threshold significance criterion ( < 4.98 × 10) for the mental phenotypes. The majority of loci was associated with schizophrenia, educational attainment, and/or intelligence. Fewer associations were found for bipolar disorder, neuroticism, attention deficit/hyperactivity disorder, major depressive disorder, depressive symptoms, and well-being. Unique associations with measures of body fat distribution adjusted for BMI were identified at five loci only. To investigate the potential causality between body fat distribution and schizophrenia, we performed two-sample Mendelian randomization analyses. We found no causal effect of body fat distribution on schizophrenia and vice versa. In conclusion, we identified 40 loci which may contribute to genetic overlaps between mental disorders/traits and BMI and/or shape related phenotypes. The majority of loci identified for body composition overlapped with BMI loci, thus suggesting pleiotropic effects.
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http://dx.doi.org/10.3389/fgene.2020.00373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186862PMC
April 2020

Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial.

Eur J Nutr 2020 Dec 27;59(8):3415-3424. Epub 2020 Feb 27.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 174, 45147, Essen, Germany.

Purpose: While observational studies revealed inverse associations between serum vitamin D levels [25(OH)D] and depression, randomized controlled trials (RCT) in children and adolescents are lacking. This RCT examined the effect of an untreated vitamin D deficiency compared to an immediate vitamin D supplementation on depression scores in children and adolescents during standard day and in-patient psychiatric treatment.

Methods: Patients with vitamin D deficiency [25(OH)D ≤ 30 nmol/l] and at least mild depression [Beck Depression Inventory II (BDI-II) > 13] (n = 113) were 1:1 randomized into verum (VG; 2640 IU vitamin D/d) or placebo group (PG) in a double-blind manner. During the intervention period of 28 days, both groups additionally received treatment as usual. BDI-II scores were assessed as primary outcome, DISYPS-II (Diagnostic System for Mental Disorders in Childhood and Adolescence, Self- and Parent Rating) and serum total 25(OH)D were secondary outcomes.

Results: At admission, 49.3% of the screened patients (n = 280) had vitamin D deficiency. Although the intervention led to a higher increase of 25(OH)D levels in the VG than in the PG (treatment difference: + 14 ng/ml; 95% CI 4.86-23.77; p = 0.003), the change in BDI-II scores did not differ (+ 1.3; 95% CI - 2.22 to 4.81; p = 0.466). In contrast, DISYPS parental ratings revealed pronounced improvements of depressive symptoms in the VG (- 0.68; 95% CI - 1.23 to - 0.13; p = 0.016).

Conclusion: Whereas this study failed to show a vitamin D supplementation effect on self-rated depression in adolescent in- or daycare patients, parents reported less depressive symptoms in VG at the end of our study. Future trials should consider clinician-rated depressive symptoms as primary outcome.

Trial Registration: "German Clinical Trials Register" ( https://www.drks.de ), registration number: DRKS00009758.
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http://dx.doi.org/10.1007/s00394-020-02176-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669774PMC
December 2020

Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies.

Addict Biol 2021 01 16;26(1):e12880. Epub 2020 Feb 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, RWTH Aachen University, Aachen, Germany.

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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http://dx.doi.org/10.1111/adb.12880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429266PMC
January 2021

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
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http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Assessing causal links between metabolic traits, inflammation and schizophrenia: a univariable and multivariable, bidirectional Mendelian-randomization study.

Int J Epidemiol 2019 10;48(5):1505-1514

Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, The Netherlands.

Background: Blood immunoreactive biomarkers, such as C-reactive protein (CRP), and metabolic abnormalities have been associated with schizophrenia. Studies comprehensively and bidirectionally probing possible causal links between such blood constituents and liability to schizophrenia are lacking.

Methods: To disentangle putative causal links between CRP blood levels and schizophrenia in both directions, we conducted multiple univariable Mendelian-randomization (MR) analyses, ranging from fixed-effect to inverse variance-weighted (IVW), weighted-median, MR Egger and generalized summary-data-based Mendelian-randomization (GSMR) models. To prioritize metabolic risk factors for schizophrenia, a novel multivariable approach was applied: multivariable Mendelian-randomization-Bayesian model averaging (MR-BMA).

Results: All forward univariable MR analyses consistently showed that CRP has a protective effect on schizophrenia, whereas reverse MR analyses consistently suggested absent causal effects of schizophrenia liability on CRP blood levels. Using MR-BMA, as the top protective factors for schizophrenia we prioritized leucine and as the prime risk-factor triglycerides in medium very-low-density lipoprotein (VLDL). The five best-performing MR-BMA models provided one additional risk factor: triglycerides in large VLDL; and two additional protective factors: citrate and lactate.

Conclusions: Our results add to a growing body of literature hinting at metabolic changes-in particular of triglycerides-independently of medication status in schizophrenia. We also highlight the absent effects of genetic liability to schizophrenia on CRP levels.
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http://dx.doi.org/10.1093/ije/dyz176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070229PMC
October 2019

Genome-wide association study identifies eight risk loci and implicates metabo-psychiatric origins for anorexia nervosa.

Nat Genet 2019 08 15;51(8):1207-1214. Epub 2019 Jul 15.

Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.

Characterized primarily by a low body-mass index, anorexia nervosa is a complex and serious illness, affecting 0.9-4% of women and 0.3% of men, with twin-based heritability estimates of 50-60%. Mortality rates are higher than those in other psychiatric disorders, and outcomes are unacceptably poor. Here we combine data from the Anorexia Nervosa Genetics Initiative (ANGI) and the Eating Disorders Working Group of the Psychiatric Genomics Consortium (PGC-ED) and conduct a genome-wide association study of 16,992 cases of anorexia nervosa and 55,525 controls, identifying eight significant loci. The genetic architecture of anorexia nervosa mirrors its clinical presentation, showing significant genetic correlations with psychiatric disorders, physical activity, and metabolic (including glycemic), lipid and anthropometric traits, independent of the effects of common variants associated with body-mass index. These results further encourage a reconceptualization of anorexia nervosa as a metabo-psychiatric disorder. Elucidating the metabolic component is a critical direction for future research, and paying attention to both psychiatric and metabolic components may be key to improving outcomes.
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http://dx.doi.org/10.1038/s41588-019-0439-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779477PMC
August 2019

Vitamin D and the Risk of Depression: A Causal Relationship? Findings from a Mendelian Randomization Study.

Nutrients 2019 May 16;11(5). Epub 2019 May 16.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany.

While observational studies show an association between 25(OH)vitamin D concentrations and depressive symptoms, intervention studies, which examine the preventive effects of vitamin D supplementation on the development of depression, are lacking. To estimate the role of lowered 25(OH)vitamin D concentrations in the etiology of depressive disorders, we conducted a two-sample Mendelian randomization (MR) study on depression, i.e., "depressive symptoms" (DS, = 161,460) and "broad depression" (BD, = 113,769 cases and 208,811 controls). Six single nucleotide polymorphisms (SNPs), which were genome-wide significantly associated with 25(OH)vitamin D concentrations in 79,366 subjects from the SUNLIGHT genome-wide association study (GWAS), were used as an instrumental variable. None of the six SNPs was associated with DS or BD (all > 0.05). MR analysis revealed no causal effects of 25(OH)vitamin D concentration, either on DS (inverse variance weighted (IVW); b = 0.025, SE = 0.038, = 0.52) or on BD (IVW; b = 0.020, SE = 0.012, = 0.10). Sensitivity analyses confirmed that 25(OH)vitamin D concentrations were not significantly associated with DS or BD. The findings from this MR study indicate no causal relationship between vitamin D concentrations and depressive symptoms, or broad depression. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.
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http://dx.doi.org/10.3390/nu11051085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566390PMC
May 2019

Melanocortin-4 Receptor and Lipocalin 2 Gene Variants in Spanish Children with Abdominal Obesity: Effects on BMI-SDS After a Lifestyle Intervention.

Nutrients 2019 Apr 26;11(5). Epub 2019 Apr 26.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Virchowstr. 174, D-45147, Essen,Germany.

Mutations leading to a reduced function of the melanocortin-4 receptor (MC4R) exert a major gene effect on extreme obesity. Recently it was shown that the bone derived hormone lipocalin 2 (LCN2) binds to the MC4R and activates a MC4R dependent anorexigenic pathway. We identified mutations in both genes and screened the effects of and mutations on eating behavior and weight change after a lifestyle intervention. One hundred and twelve children (11.24 ± 2.6 years, BMI-SDS 2.91 ± 1.07) with abdominal obesity participated in a lifestyle intervention. and coding regions were screened by Sanger sequencing. Eating behavior was assessed at baseline with the Children Eating Behavior Questionnaire (CEBQ). We detected three previously described non-synonymous variants (Glu42Lys, Thr150Ile, and Arg305Gln) and one non-synonymous polymorphism (Ile251Leu). Regarding , one known non-synonymous variant (Thr124Met) was detected. Eating behavior was described in carriers of the and mutation and in non-carriers. and mutations were detected in 2.42% and 0.84%, respectively, of Spanish children with abdominal obesity. A number of subjects with functional mutation variants in and were able to achieve a reduction in BMI-SDS after a lifestyle intervention.
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http://dx.doi.org/10.3390/nu11050960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566731PMC
April 2019

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

Am J Psychiatry 2019 03;176(3):217-227

The Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Department of Psychiatry, Massachusetts General Hospital, Boston (Yu, Illmann, Osiecki, Smoller, Pauls, Neale, Scharf); the Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Mass. (Yu, Neale, Scharf); the Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, University of California, Los Angeles (Sul, Huang, Zelaya, Ophoff, Freimer, Coppola); the Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles (Sul, Huang, Zelaya, Freimer, Coppola); the Department of Molecular Biology and Genetics, Democritus University of Thrace, Xanthi, Greece (Tsetsos); the Department of Biological Sciences, Purdue University, West Lafayette, Ind. (Tsetsos, Paschou); deCODE Genetics/Amgen, Reykjavik, Iceland (Nawaz, H. Stefansson, K. Stefansson); the Bioinformatics Interdepartmental Program, University of California, Los Angeles (Huang, Zelaya); the Department of Psychiatry, University of California, San Francisco (Darrow); the Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California, San Francisco (Hirschtritt, Willsey); the Department of Psychiatry, Massachusetts General Hospital, Boston (Greenberg, Roffman, Buckner); the Clinic of Psychiatry, Social Psychiatry, and Psychotherapy, Hannover Medical School, Hannover, Germany (Muller-Vahl); the Institute of Human Genetics, Hannover Medical School, Hannover, Germany (Stuhrmann); McGill University Health Center, University of Montreal, McGill University Health Centre, Montreal (Dion); the Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal (Rouleau); the Department of Psychiatry and Psychotherapy, Medical University Vienna, Vienna (Aschauer, Stamenkovic); Biopsychosocial Corporation, Vienna (Aschauer, Schlögelhofer); University Health Network, Youthdale Treatment Centres, and University of Toronto, Toronto (Sandor); the Krembil Research Institute, University Health Network, Hospital for Sick Children, and University of Toronto, Toronto (Barr); Johns Hopkins University School of Medicine, Baltimore (Grados, Singer); the Institute of Human Genetics, University Hospital Bonn, University of Bonn Medical School, Bonn, Germany (Nöthen); the Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (Hebebrand, Hinney); the Yale Child Study Center and the Department of Psychiatry, Yale University School of Medicine, New Haven, Conn. (King, Fernandez); the Institute of Medical Chemistry, Molecular Biology, and Pathobiochemistry, Semmelweis University, Budapest, Hungary (Barta); Vadaskert Child and Adolescent Psychiatric Hospital, Budapest, Hungary (Tarnok, Nagy); the Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany (Depienne); Sorbonne Universités, UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225, ICM, Paris (Depienne, Worbe, Hartmann); French Reference Centre for Gilles de la Tourette Syndrome, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Assistance Publique-Hôpitaux de Paris, Department of Neurology, Groupe Hospitalier Pitié-Salpêtrière, Paris (Worbe, Hartmann); Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York (Budman); Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy (Rizzo); the Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (Lyon); the Department of Psychiatry, University of Utah, Salt Lake City (McMahon); Children's Mercy Hospital, Kansas City, Mo. (Batterson); the Department of Psychiatry, University Medical Center Groningen and Rijksuniversity Groningen, and Drenthe Mental Health Center, Groningen, the Netherlands (Cath); the Department of Neurology, Fixel Center for Neurological Diseases, McKnight Brain Institute, University of Florida, Gainesville (Malaty, Okun); Pennsylvania State University College of Medicine, Hershey (Berlin); Marquette University and University of Wisconsin-Milwaukee, Milwaukee (Woods); Tripler Army Medical Center and University of Hawaii John A. Burns School of Medicine, Honolulu (Lee); Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston (Jankovic); the Division of Psychiatry, Department of Neuropsychiatry, University College London (Robertson); the Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati (Gilbert); Children's Hospital of Philadelphia, Philadelphia (Brown); the Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami (Coffey); the Department of Child and Adolescent Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands (Dietrich, Hoekstra); University of Iowa Carver College of Medicine, Iowa City (Kuperman); the Department of Pediatrics, University of Washington, Seattle (Zinner); the Department of Pediatrics, Landspitalinn University Hospital, Reykjavik, Iceland (Luðvigsson, Thorarensen); the Faculty of Medicine, University of Iceland, Reykjavík, Iceland (Sæmundsen, Stefansson); the State Diagnostic and Counselling Centre, Kópavogur, Iceland (Sæmundsen); the Department of Genetics and the Department of Medicine, Albert Einstein College of Medicine, Bronx, New York (Atzmon, Barzilai); the Department of Human Biology, Haifa University, Haifa, Israel (Atzmon); the Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany (Wagner); the Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany (Moessner); SUNY Downstate Medical Center Brooklyn, New York (C.M. Pato, M.T. Pato, Knowles); the Athinoula A. Martinos Center for Biomedical Research, Department of Radiology, Massachusetts General Hospital, Charlestown (Roffman, Buckner); the Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston (Smoller); the Center for Brain Science and Department of Psychology, Harvard University, Cambridge, Mass. (Buckner); the Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco (Willsey); the Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers, the State University of New Jersey, Piscataway (Tischfield, Heiman); the Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU University Amsterdam, Amsterdam (Posthuma); the Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, Tenn. (Cox, Davis); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston (Neale); the Department of Psychiatry, Genetics Institute, University of Florida, Gainesville (Mathews); and the Department of Neurology, Brigham and Women's Hospital, and the Department of Neurology, Massachusetts General Hospital, Boston (Scharf).

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity.

Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined.

Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects.

Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.
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http://dx.doi.org/10.1176/appi.ajp.2018.18070857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677250PMC
March 2019

The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: Association study and meta-analysis.

Am J Med Genet B Neuropsychiatr Genet 2019 09 25;180(6):365-376. Epub 2018 Nov 25.

Department of Child and Adolescent Psychiatry and Psychotherapy, University Hospital of Psychiatry Zurich, University of Zurich, Zurich, Switzerland.

Wnt-signaling is one of the most abundant pathways involved in processes such as cell-proliferation, -polarity, and -differentiation. Altered Wnt-signaling has been linked with several neurodevelopmental disorders including attention-deficit/hyperactivity disorder (ADHD) as well as with cognitive functions, learning and memory. Particularly, lipoprotein receptor-related protein 5 (LRP5) or LRP6 coreceptors, responsible in the activation of the canonical Wnt-pathway, were associated with cognitive alterations in psychiatric disorders. Following the hypothesis of Wnt involvement in ADHD, we investigated the association of genetic variations in LRP5 and LRP6 genes with three independent child and adolescent ADHD (cADHD) samples (total 2,917 participants), followed by a meta-analysis including previously published data. As ADHD is more prevalent in males, we stratified the analysis according to sex and compared the results with the recent ADHD Psychiatric Genomic Consortium (PGC) GWAS. Meta-analyzing our data including previously published cADHD studies, association of LRP5 intronic rs4988319 and rs3736228 (Ala1330Val) with cADHD was observed among girls (OR = 1.80 with 95% CI = 1.07-3.02, p = .0259; and OR = 2.08 with 95% CI = 1.01-4.46, p = .0026, respectively), whereas in boys association between LRP6 rs2302685 (Val1062Ile) and cADHD was present (OR = 1.66, CI = 1.20-2.31, p = .0024). In the PGC-ADHD dataset (using pooled data of cADHD and adults) tendency of associations were observed only among females with OR = 1.09 (1.02-1.17) for LRP5 rs3736228 and OR = 1.18 (1.09-1.25) for LRP6 rs2302685. Together, our findings suggest a potential sex-specific link of cADHD with LRP5 and LRP6 gene variants, which could contribute to the differences in brain maturation alterations in ADHD affected boys and girls, and suggest possible therapy targets.
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http://dx.doi.org/10.1002/ajmg.b.32695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767385PMC
September 2019

The association of serum leptin levels with food addiction is moderated by weight status in adolescent psychiatric inpatients.

Eur Eat Disord Rev 2018 11 4;26(6):618-628. Epub 2018 Sep 4.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Leptin is essential for the control of energy homeostasis and eating behaviour. We investigated potential associations between serum leptin levels and food addiction in adolescent psychiatric inpatients (n = 228). The most frequent psychiatric diagnoses were mood disorders, anxiety disorders, and substance use disorders. More than three quarters of the study group suffered from more than one psychiatric disorder. Food addiction was assessed with the Yale Food Addiction Scale. Leptin was determined in serum. Analyses were conducted for the whole body weight range and for distinct weight categories to evaluate a potential impact of known nonlinearity between leptin levels and satiety due to leptin resistance in obese. A weak negative association between food addiction and leptin in normal weight patients (ß = -0.11, p = .022) was detected. In contrast, food addiction was associated with a significantly higher serum leptin (ß = 0.16. p = .038) in overweight patients. Food addiction in normal weight patients might be associated with restrained eating, previously shown to involve reduced leptin levels. The small positive association of food addiction with higher serum leptin in overweight patients might reflect leptin resistance and overeating.
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http://dx.doi.org/10.1002/erv.2637DOI Listing
November 2018

Relevance of polymorphisms in MC4R and BDNF in short normal stature.

BMC Pediatr 2018 08 22;18(1):278. Epub 2018 Aug 22.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition.

Methods: We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants.

Results: We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS.

Conclusion: Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature.
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http://dx.doi.org/10.1186/s12887-018-1245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106737PMC
August 2018

Waist-hip ratio related genetic loci are associated with risk of impaired fasting glucose in Chinese children: a case control study.

Nutr Metab (Lond) 2018 3;15:34. Epub 2018 May 3.

1Department of Maternal and Child Health, School of Public Health, Peking University, No.38 Xueyuan Road, Haidian District, Beijing, 100191 China.

Background: The meta-analyses of genome-wide association studies identified several waist-hip ratio (WHR) related loci in individuals of European ancestry. Since the pattern of fat distribution and the relationship between fat distribution and glucose metabolism disturbance in Chinese are different from those in Europeans, the present study aimed to explore the individual and cumulative effects of WHR-related loci on glycemic phenotypes in Chinese children.

Methods: A total of 2030 children were recruited from two independent studies. Eleven single nucleotide polymorphisms (SNPs) were selected and genotyped using matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Logistic regression and linear regression model were used to examine the association of 11 SNPs and genetic risk score (GRS) with impaired fasting glucose (IFG) and fasting plasma glucose (FPG), respectively.

Results: Three SNPs (rs6795735, rs984222 and rs1011731) were nominally associated with IFG (all  < 0.05). Each WHR-increasing (C) allele of rs6795735 () was associated with a 40.1% increased risk of IFG (OR = 1.401, 95% CI = 1.131-1.735,  = 0.002), which remained significant after Bonferroni correction. We observed no association of both weighted and unweighted GRS with FPG and IFG (all  > 0.05).

Conclusions: We identified individual effects of rs6795735 (), rs984222 (), and rs1011731 () on glycemic phenotypes in Chinese children for the first time. The study suggests that genetic predisposition to central obesity is associated with impaired fasting glucose, providing more evidence for the pathogenesis of diabetes.
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http://dx.doi.org/10.1186/s12986-018-0270-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934898PMC
May 2018

The role of genetic variation of human metabolism for BMI, mental traits and mental disorders.

Mol Metab 2018 06 3;12:1-11. Epub 2018 Apr 3.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Essen, Germany. Electronic address:

Objective: The aim was to assess whether loci associated with metabolic traits also have a significant role in BMI and mental traits/disorders METHODS: We first assessed the number of single nucleotide polymorphisms (SNPs) with genome-wide significance for human metabolism (NHGRI-EBI Catalog). These 516 SNPs (216 independent loci) were looked-up in genome-wide association studies for association with body mass index (BMI) and the mental traits/disorders educational attainment, neuroticism, schizophrenia, well-being, anxiety, depressive symptoms, major depressive disorder, autism-spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's disease, bipolar disorder, aggressive behavior, and internalizing problems. A strict significance threshold of p < 6.92 × 10 was based on the correction for 516 SNPs and all 14 phenotypes, a second less conservative threshold (p < 9.69 × 10) on the correction for the 516 SNPs only.

Results: 19 SNPs located in nine independent loci revealed p-values < 6.92 × 10; the less strict criterion was met by 41 SNPs in 24 independent loci. BMI and schizophrenia showed the most pronounced genetic overlap with human metabolism with three loci each meeting the strict significance threshold. Overall, genetic variation associated with estimated glomerular filtration rate showed up frequently; single metabolite SNPs were associated with more than one phenotype. Replications in independent samples were obtained for BMI and educational attainment.

Conclusions: Approximately 5-10% of the regions involved in the regulation of blood/urine metabolite levels seem to also play a role in BMI and mental traits/disorders and related phenotypes. If validated in metabolomic studies of the respective phenotypes, the associated blood/urine metabolites may enable novel preventive and therapeutic strategies.
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http://dx.doi.org/10.1016/j.molmet.2018.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001916PMC
June 2018

The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus.

Obes Facts 2018 10;11(2):93-108. Epub 2018 Apr 10.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Objective: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level.

Methods: We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student’s t-test for independent samples was applied and effect sizes using Cohen’s d were calculated.

Results: In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values ≤ 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p ≤ 0.05), three resulted in p values ≤ 0.01 ( Cap1 (150Arg; d = 7.48), Mapk1 (343Met; d = –6.80) and Sorbs1 (689Leu; d = 7.82)).

Conclusion: The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling.
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http://dx.doi.org/10.1159/000486962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5981666PMC
September 2019

Effect of an vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients - a randomized controlled trial: study protocol.

BMC Psychiatry 2018 03 1;18(1):57. Epub 2018 Mar 1.

Department of Child and Adolescent Psychiatry, University Hospital Essen, University of Duisburg-Essen, Wickenburgstr. 21, D-45147, Essen, Germany.

Background: Depression is a significant health and economic burden worldwide affecting not only adults but also children and adolescents. Current treatment options for this group are scarce and show moderate effect sizes. There is emerging evidence that dietary patterns and specific nutritional components might play a role in the risk for developing depression. This study protocol focusses on the role of vitamin D which is for long known to be relevant for calcium and phosphorous homeostasis and bone health but might also impact on mental health. However, the assessment of the vitamin D status of depressed juvenile patients, or supplementation of vitamin D is currently not part of routine treatment. Controlled intervention studies are indispensable to prove whether a vitamin D deficiency ameliorates depressive symptoms.

Methods/design: This double blinded, randomized controlled trial will enroll 200 inpatients from a child and adolescent psychiatric department with a vitamin D deficiency defined by a 25(OH)-vitamin D-level < 30 nmol/l (12 ng/ml) and a Beck Depressions Inventory (BDI-II) score > 13 (indicating at least: mild depression). Upon referral, all patients will be screened, checked for inclusion criteria, and those eligible will be randomized after written consent into a supplementation or placebo group. Both study-arms will receive treatment-as-usual for their psychiatric disorder according to established clinical guidelines. The participants of the vitamin D supplementation group will receive 2640 I.E. vitamin D3 q.d. for 28 days in accordance with best practice in pediatric endocrinology. We hypothesize that delaying supplementation of vitamin D in the placebo arm will affect the treatment success of the depressive symptomatology in comparison to the vitamin D supplementation group. Patients will be enrolled for a period of 28 days based on the mean length of hospitalization of juveniles with depression.

Discussion: Randomized controlled trials in children and adolescents with depression are needed to elucidate the role of a vitamin D deficiency for mental disorders and to investigate the relevance of a routine assessment and supplementation of vitamin D deficits.

Trial Registration: DRKS00009758, 16/06/2016 (retrospectively registered).
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http://dx.doi.org/10.1186/s12888-018-1637-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831612PMC
March 2018

Estimated prevalence of potentially damaging variants in the leptin gene.

Mol Cell Pediatr 2017 Nov 3;4(1):10. Epub 2017 Nov 3.

Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Eythstr. 24, D-89075, Ulm, Germany.

Background: Mutations in the leptin gene (LEP) can alter the secretion or interaction of leptin with its receptor, leading to extreme early-onset obesity. The purpose of this work was to estimate the prevalence of heterozygous and homozygous mutations in the leptin gene with the help of the Exome Aggregation Consortium (ExAC) database ( http://exac.broadinstitute.org/about ).

Results: The ExAC database encompasses exome sequencing data from 60,706 individuals. We searched for listed leptin variants and identified 36 missense, 1 in-frame deletion, and 3 loss-of-function variants. The functional relevance of these variants was assessed by the in silico prediction tools PolyPhen-2, Sorting Intolerant from Tolerant (SIFT), and Loss-Of-Function Transcript Effect Estimator (LOFTEE). PolyPhen-2 predicted 7 of the missense variants to be probably damaging and 10 to be possibly damaging. SIFT predicted 7 of the missense variants to be deleterious. Three loss-of-function variants were predicted by LOFTEE. Excluding double counts, we can summarize 21 variants as potentially damaging. Considering the allele count, we identified 31 heterozygous but no homozygous subjects with at least probably damaging variants. In the ExAC population, the estimated prevalence of heterozygous carriers of these potentially damaging variants was 1:2000. The probability of homozygosity was 1:15,000,000. We furthermore tried to assess the functionality of ExAC-listed leptin variants by applying a knowledge-driven approach. By this approach, additional 6 of the ExAC-listed variants were considered potentially damaging, increasing the number of heterozygous subjects to 58, the prevalence of heterozygosity to 1:1050, and the probability of homozygosity to 1:4,400,000.

Conclusion: Using exome sequencing data from ExAC, in silico prediction tools and by applying a knowledge-driven approach, we identified 27 probably damaging variants in the leptin gene of 58 heterozygous subjects. With this information, we estimate the prevalence for heterozygosity at 1:1050 corresponding to an incidence of homozygosity of 1:4,400,000 in this large pluriethnic cohort.
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http://dx.doi.org/10.1186/s40348-017-0074-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670095PMC
November 2017

Rare Variant Analysis of Human and Rodent Obesity Genes in Individuals with Severe Childhood Obesity.

Sci Rep 2017 06 29;7(1):4394. Epub 2017 Jun 29.

University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

Obesity is a genetically heterogeneous disorder. Using targeted and whole-exome sequencing, we studied 32 human and 87 rodent obesity genes in 2,548 severely obese children and 1,117 controls. We identified 52 variants contributing to obesity in 2% of cases including multiple novel variants in GNAS, which were sometimes found with accelerated growth rather than short stature as described previously. Nominally significant associations were found for rare functional variants in BBS1, BBS9, GNAS, MKKS, CLOCK and ANGPTL6. The p.S284X variant in ANGPTL6 drives the association signal (rs201622589, MAF~0.1%, odds ratio = 10.13, p-value = 0.042) and results in complete loss of secretion in cells. Further analysis including additional case-control studies and population controls (N = 260,642) did not support association of this variant with obesity (odds ratio = 2.34, p-value = 2.59 × 10), highlighting the challenges of testing rare variant associations and the need for very large sample sizes. Further validation in cohorts with severe obesity and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity. Such studies may yield druggable targets for weight loss therapies.
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http://dx.doi.org/10.1038/s41598-017-03054-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491520PMC
June 2017
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